The overall goal of the study is to understand the mechanisms of the development and regulation of lung inflammation and fibrosis. In particular, the focus has been on the role of the alveolar macrophage in the etiology of lung diseases caused by environmental and occupational agents such as silica, asbestos, ozone, acrolein and urban particulate matter. The overall hypothesis of the studies is that environmental agents cause preferential apoptosis of immune suppressor macrophages (RFD1,7 epitopes), allowing the minor population of dendritic-like immune active macrophages (RFD1 epitope) to initiate lung inflammation through activation of T helper cell pathways and the immune cascade. Previous studies have demonstrated that immune suppressor macrophages are more sensitive to apoptosis than immune active macrophages in response to all the particulate agents. In addition, the particulates bind to scavenger receptors on alveolar macrophages to stimulate signal transduction pathways leading to activation of caspases, MAPkinases and JNKinases involved in apoptosis. Consequently, scavenger receptors appear to be integral in the initiation of the inflammatory cascade through apoptosis of RFD1,7 macrophages. Future studies are planned to isolate and characterize the macrophage subpopulations as well as the epitopes defined by the antibodies against RFD1 and RFD7. These studies will confirm the presence of distinct macrophage populations and the proteins that describe the populations. In addition, studies will also examine the function of the RFD proteins. Studies will also examine the roles of these macrophage populations in patients with lung fibrosis and test for the presence of autoimmune antibodies that are proposed to form from apoptotic bodies taken up by the immune competent macrophage population. All together, these studies will establish that chronic lung inflammation is caused by a disregulation of the lung immune system. An improved knowledge of the etiology of this disease should allow the development of improved treatment strategies.